Biphenyl compound selective agonists of gamma RAR receptors

ABSTRACT

Biphenyl compounds having the formula (I): 
                         
are useful for preventing/treating pathologies linked to a deficiency of the activation of the RAR gamma receptor, e.g., for treating a pathology linked to a cell differentiation and/or proliferation disorder, for treating acne, for treating psoriasis.

CROSS-REFERENCE TO PRIORITY/PCT APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/213,177, filed Jun. 16, 2008 and claims priority under 35 U.S.C. §119of FR 0512760, filed Dec. 15, 2005, and is a continuation of PCT/EP2006/068976, filed Nov. 28, 2006, and designating the United States(published in the French language on Jun. 21, 2007, as WO 2007/068580A1; the title and abstract were also published in English), each herebyexpressly incorporated by reference in its entirety and each assigned tothe assignee hereof.

CROSS-REFERENCE TO COMPANION APPLICATIONS

Copending U.S. application Ser. No. 12/213,178, filed Jun. 16, 2008,hereby expressly incorporated by reference and also assigned to theassignee hereof.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The present invention relates to the therapeutic administration, inparticular in the dermatology field, of novel biphenyl compoundssubstituted with an aromatic radical having selective activity for thegamma subtype of the RAR receptor family.

2. Description of Background and/or Related and/or Prior Art

A family of biphenyl compounds has been described in WO 99/10308. Thesecompounds are described as having an application in the topical andsystemic treatment of dermatological conditions linked to akeratinization disorder, and of ophthalmological conditions inparticular.

The activity of these compounds has in particular been demonstrated bymeans of tests for differentiation of mouse embryonic teratocarcinoma F9cells and keratinocyte differentiation tests in humans.

On the other hand, this publication in no way makes any reference to apossible specific activity of the compounds with respect to the gammasubtype of RAR receptors.

Indeed, the gamma subtype of the RAR receptor family is largelypredominant in the epidermis, where it represents approximately 90% ofthe total receptors (“Retinoic acid receptors and binding proteins inhuman skin”, Elder J T, Astrom A, Pettersson U, Tavakkol A, Krust A,Kastner P, Chambon P, Voorhees J. J.: J. Invest. Dermatol., 1992; 98 (6Suppl): 36S-41S; or “Retinoic acid receptor expression in human skinkeratinocytes and dermal fibroblasts in vitro”, Redfern C P, Todd C. J.Cell Sci., 1992; 102 (Pt 1): 113-21), and it is indeed the interactionwith this RAR gamma receptor which is responsible for the effectivenessof retinoids on the epidermis (“Retinoic acid receptor gamma mediatestopical retinoid efficacy and irritation in animal models”, Chen S,Ostrowski J, Whiting G, Roalsvig T, Hammer L, Currier S J, Honeyman J,Kwasniewski B, Yu K L, Sterzycki R, et al., J. Invest. Dermatol., 1995;104 (5): 779-83).

RAR gamma receptors are therefore the sole target in the treatment ofpathologies at the epidermal level, for instance for acne or psoriasisor any other skin pathology treated with retinoids.

Furthermore, certain side effects specific to RAR alpha or RAR beta canbe avoided if compounds having a selective action on RAR gamma are used.

SUMMARY OF THE INVENTION

It has now surprisingly been shown that the compounds according to theinvention have an extremely advantageous selective agonist activity forthe gamma subtype of the RAR receptor family.

The compounds according to the invention, selective agonists of the RARgamma subtype, thus make it possible to prevent and/or treat variousdermatological pathologies or disorders, while at the same timedecreasing the side effects normally caused by the action of the activeagents on the RAR alpha and beta subtypes.

The present invention therefore features compounds having the followinggeneral formula:

in which n is an integer ranging from 1 to 3 inclusive, thus equal to 1,2 or 3, and also the salts of the compounds of formula (I).

According to a preferred embodiment, n is equal to 2 or 3, and thepreferred compounds of formula (I) are selected from4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid and4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid.

The term “pharmaceutically acceptable salt” means an alkali metal salt,or an alkaline-earth metal salt, or an organic amine salt.

The present invention also features the formulation of at least onecompound of formula (I), into pharmaceutical or cosmetic compositionsuseful in preventing and/or treating pathologies for which a selectiveagonist activity for the gamma subtype of the RAR receptor family isdesired.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE of Drawing is a reaction scheme illustrating preparation ofthe compounds according to the present invention.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

A general synthetic pathway for preparing the compounds of formula (I)is represented in the scheme shown in the FIGURE of Drawing.

The starting materials and/or the reactants employed are commerciallyavailable and/or can be prepared according to known methods in theliterature.

According to another embodiment, the present invention also features aprocess for preparing the compounds of formula (I) described above,comprising the following steps:

-   -   i) coupling reaction, preferably of Suzuki reaction type, from        the compound of formula 1 prepared, for example, as described in        WO 99/10308:

and the compound of formula 2 prepared, for example, as described in WO99/10308:

to produce the compound of formula 3

-   -   ii) etherification reaction, for example of the Williamson        etherification type or the like (see, for example, Lerman, L et        al.; Synthesis 2004, (18), 3043-3046), of the compound of        formula 3 with the compound of formula 4,

in which X represents a leaving group allowing a nucleophilicsubstitution, for instance a halogen (preferably, an iodine or bromineatom), R represents a hydrogen or a suitable protective group asdescribed in “Protective Groups in Organic Synthesis” (Greene & Wuts,Wiley-Interscience 1991), for example acetyl ordimethyl-tert-butylsilyl, and n is an integer ranging from 1 to 3,preferably 2 or 3, to produce the compound of formula 5:

-   -   iii) in the case where R is other than H, this reaction ii) is        followed by a reaction for deprotection of the alcohol function        of the compound of formula 5, to produce the compound of formula        6:

-   -   iv) saponification of the ester function of the compound        obtained in the preceding step, i.e. step ii) for cases where        R═H, or step iii) for cases where R is other than H, to produce        the corresponding compound of formula (I) (compound 7 in the        FIGURE of Drawing).

Step i) may, for example, be carried out in the presence of potassiumcarbonate and of tetrakis(triphenylphosphine)palladium in a toluenesolution.

Step ii) may, for example, be carried out in the presence of cesiumcarbonate and of dimethylformamide and, optionally, of potassium iodide.

Step iii) may be carried out in accordance with the deprotectionreactions described in “Protective Groups in Organic Synthesis” (Greene& Wuts, Wiley-Interscience 1991).

Step iv) may, for example, be carried out in the presence of sodiumhydroxide and of THF.

The present invention also features administration of the compounds offormula (I) as described above, as a medicament.

According to another embodiment, this invention features pharmaceuticalor cosmetic compositions, comprising, formulated into a pharmaceuticallyor cosmetically acceptable carrier, at least one compound of formula(I).

The term “pharmaceutically or cosmetically acceptable carrier” means acarrier suitable for use in contact with human and animal cells, with notoxicity, irritation, undue allergic response, and the like, andproportional to a reasonable advantage/risk ratio.

The administration may be carried out topically, enterally or orally,parenterally or ocularly, whether regime or regimen. Among these routesof administration, topical administration is particularly preferred.

When administered topically, the pharmaceutical compositions accordingto the invention are more particularly useful in the treatment of theskin and mucous membranes and may be in liquid, pasty or solid form, andmore particularly in the form of salves, creams, milks, ointments,powders, impregnated pads, syndets, solutions, gels, sprays, mousses,suspensions, sticks, shampoos or washing bases. Same may also be in theform of suspensions of lipid or polymeric vesicles or microspheres ornanospheres, or polymeric or gelled patches for controlled release.

The compounds are employed topically at a concentration generally offrom 0.001% and 3% by weight, relative to the total weight of thecomposition.

For cosmetic applications, the compositions are preferably in the formof a cream, a milk, a lotion, a gel, lipid or polymeric vesicles ormicrospheres or nanospheres, a soap or a shampoo.

When administered enterally or orally, the compositions may be in theform of tablets, gel capsules, sugar-coated tablets, syrups,suspensions, solutions, powders, granules, emulsions, or suspensions oflipid or polymeric vesicles or microspheres or nanospheres forcontrolled release. When administered parenterally, the compositions maybe in the form of solutions or suspensions for perfusion or forinjection.

The compounds according to the invention are generally administered at adaily dose of approximately 0.01 mg/kg to 30 mg/kg of body weight, takenin 1 to 3 doses.

The compounds of the invention can be formulated, alone or as a mixture,into pharmaceutical compositions useful in the treatment and/orprevention of pathologies linked to a deficiency in the activation ofthe RAR gamma receptor.

This invention also features a method of therapeutic or cosmetictreatment, comprising the administration of a pharmaceutical or cosmeticcomposition comprising at least one compound of formula (I), saidcompound exercising a selective agonist activity for the RAR gammareceptor.

The pharmaceutical compositions may be more particularly useful intreating a pathology for which the treatment requires a selectiveagonist activity for the RAR gamma receptor, more particularly at thelevel of the epithelial tissues, the skin and the bones.

The compositions can in particular be administered for the treatment ofa pathology linked to cell differentiation and/or proliferationdisorders, in particular in the dermatology field.

More particularly, same are useful in the treatment of a pathologylinked to a keratinization disorder.

The treatment of acne is thus envisioned, in particular common acne,comedone acne, polymorphic acne, nodulocystic acne, acne conglobata,senile acne, secondary acne such as solar acne, acne medicamentosa oroccupational acne.

The pharmaceutical compositions comprising a compound of formula (I) arealso useful in the treatment of other dermatological conditions linkedto a keratinization disorder with an inflammatory and/or immunoallergiccomponent, and in particular all forms of psoriasis, whether cutaneous,mucosal or ungula.

The compounds according to the invention can also be formulated intocosmetic compositions, for combating skin aging, whether for examplephotoinduced or chronological.

The pharmaceutical or cosmetic compositions are also useful to regulateskin pigmentations and to treat actinic keratoses.

In all the applications envisioned, said compounds may be combined withanother therapeutic agent that can be used in the treatment of apathology linked to cell differentiation or proliferation disorders.

As therapeutic agents that can be included in the compositions accordingto the invention, exemplary are agents for modulating skindifferentiation and/or proliferation and/or pigmentation, such asretinoic acid and its isomers, retinol and its esters, retinal,retinoides, estrogens, antibacterial agents, antibiotics, anti-parasiticagents, antifungal agents, steroidal or non-steroidal anti-inflammatoryagents, anesthetics, anti-pruriginous agents, antiviral agents,keratolytic agents, free-radical scavengers, anti-seborrheic agents,antidandruff agents, anti-acne agents, agents for combating hair loss,and vitamin C and its derivatives, with the proviso, as is indicatedabove, that the active agents be in solubilized form in the compositionaccording to the invention.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended only as illustrative and in nowise limitative. Insaid examples to follow, all parts and percentages are given by weight,unless otherwise indicated.

In the examples hereinafter, the samples were analyzed by ¹H NMR, ¹³CNMR and HPLC/MS.

EXAMPLE 1 Synthesis of4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid a) Preparation of ethyl4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate

10 g (31 mmol) of ethyl 3′-bromo-4′-hydroxybiphenyl-4-carboxylate(prepared according to EP952974), 8.7 g (37 mmol) of6-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene)boronic acid(prepared according to EP952974) and 34 ml (74.6 mmol) of a 2M aqueoussolution of potassium carbonate are placed in 200 ml of toluene, in athree-necked flask, and then 1.8 g (1.55 mmol) oftetrakis(triphenylphosphine)palladium are added under nitrogen. Thereaction mixture is heated for 24 h at 110° C. After cooling, thereaction is stopped by adding 200 ml of water and then extracted withethyl acetate. The organic phases are combined, washed with a saturatedsolution of sodium chloride and dried over magnesium sulfate. Thesolvents are evaporated off and the residue is then chromatographed onsilica gel (80/20 heptane/ethyl acetate). 8 g of ethyl4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylateare obtained in the form of a white solid (yield=60%).

b) Preparation of ethyl4′-[4-(tert-butyldimethylsilanyloxy)propoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate

A solution of 2.1 g (4.9 mmol) of ethyl4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylateis introduced into 24 ml of dimethylformamide, in a three-necked flask,and then 1.9 g (5.9 mmol) of cesium carbonate, 1.33 ml (5.9 mmol) oftert-butyl-4-iodopropoxy)dimethylsilane and 0.24 g (1.44 mmol) ofpotassium iodide are added. The reaction mixture is heated for 6 h at80° C. After cooling, the reaction mixture is filtered in order toremove the cesium carbonate (rinsing with ethyl acetate). The filtrateis evaporated off under vacuum. The crude obtained in the form of an oilis chromatographed on silica gel (heptane/ethyl acetate: 95/5), to give2.75 g of ethyl4′-[4-(tert-butyldimethylsilanyloxy)propoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylatein the form of a colorless oil (yield=93%).

c) Preparation of ethyl4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate

6.9 ml (6.9 mmol) of a solution of tetrabutylammonium fluoride (1 M) areadded to a solution of 2.75 g (4.6 mmol) of ethyl4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylatein 20 ml of tetrahydrofuran, in a three-necked flask. The reactionmixture is stirred for 4 h at ambient temperature. The reaction isstopped by adding 20 ml of water and the mixture is then extracted withethyl acetate. The organic phases are combined, washed with a saturatedaqueous solution of sodium chloride, and dried over magnesium sulfate.The solvents are evaporated off. The crude obtained in the form of anoil is chromatographed on silica gel (heptane/ethyl acetate: 70/30) togive 2 g of ethyl4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylatein the form of a colorless oil (yield=89%).

d) Synthesis of4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenylcarboxylicacid

2.05 ml (2.05 mmol) of an aqueous solution of sodium hydroxide (1 M) areadded to a solution of 0.20 g (0.41 mmol) of ethyl4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylatein 5 ml of tetrahydrofuran. The reaction mixture is stirred for 48 hwhile heating at 40° C. The reaction mixture is placed under a stream ofnitrogen in order to eliminate the tetrahydrofuran and then 2.5 ml (2.5mmol) of a solution of hydrochloric acid (1 M) are added. The productprecipitates in the form of a white solid. After filtration, the productis washed twice with 5 ml of diethyl ether and then placed in an ovenunder vacuum overnight. 0.17 g of4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid is obtained (white solid, Mp=317° C., yield=90%).

¹H NMR (DMSO, 400 MHz): 1.26 (s, 12H); 1.6 (s, 4H); 1.90 (t, J=6.2 Hz,2H); 3.8 (t, J=6.0 Hz, 2H); 4.09 (t, J=6.3 Hz, 2H); 7.05 (d, J=9.2 Hz,1H); 7.25-7.29 (m, 2H); 7.50-7.52 (m, 5H); 8.01 (d, J=8.2 Hz, 2H).

EXAMPLE 2 Synthesis of4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid a) Preparation of ethyl4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate

A solution of 2.1 g (4.9 mmol) of ethyl4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate(prepared according to Example 1, step a) is introduced into 24 ml ofdimethylformamide, in a three-necked flask, then 1.9 g (5.9 mmol) ofcesium carbonate and 1.53 ml (5.9 mmol) oftert-butyl-(4-iodobutoxy)dimethylsilane are added. The reaction mixtureis heated for 6 h at 80° C. After cooling, the reaction mixture isfiltered in order to remove the cesium carbonate (rinsing with ethylacetate). The filtrate is evaporated under vacuum. The crude obtained inthe form of an oil is chromatographed on silica gel (heptane/ethylacetate: 95/5), to give 2.8 g of ethyl4′-[4-tert-butyldimethylsilanyloxy)butoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylatein the form of a colorless oil (yield=93%).

b) Preparation of ethyl4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate

6.8 ml (6.8 mmol) of a solution of tetrabutylammonium fluoride (1 M) areadded to a solution of 2.8 g (4.5 mmol) of ethyl4′-[4-(tert-butyldimethylsilanyloxy)butoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylatein 20 ml of tetrahydrofuran. The reaction mixture is stirred for 4 h atambient temperature. The reaction is stopped by adding 20 ml of waterand the mixture is then extracted with ethyl acetate. The organic phasesare combined, washed with a saturated aqueous solution of sodiumchloride, and dried over magnesium sulfate. The solvents are evaporatedoff. The crude obtained in the form of an oil is chromatographed onsilica gel (heptane/ethyl acetate: 70/30), to give 2.10 g of ethyl4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylatein the form of a colorless oil (yield=93%).

c) Synthesis of4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid

2 ml (2.0 mmol) of an aqueous solution of sodium hydroxide (1 M) areadded to a solution of 0.20 g (0.40 mmol) of ethyl4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylatein 8 ml of tetrahydrofuran. The reaction mixture is stirred for 48 hwhile heating at 40° C. The reaction mixture is placed under a stream ofnitrogen in order to eliminate the tetrahydrofuran and then 2.4 ml (2.4mmol) of a solution of hydrochloric acid (1 M) are added. The productprecipitates in the form of a white solid. After filtration, the productis washed twice with 5 ml of diethyl ether and then dried in an ovenunder vacuum overnight. 0.17 g of4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid is obtained (white solid, Mp 235° C., yield=90%).

¹H NMR (DMSO, 400 MHz): 1.24 (s, 12H); 1.56 (m, 2H); 1.64 (s, 4H); 1.78(m, 2H); 3.48 (t, J=6.4 Hz, 2H); 3.99 (t, J=6.5 Hz, 2H); 7.60 (d, J=8.5Hz, 1H); 7.24-7.27 (m, 2H); 7.46-7.53 (m, 5H); 8.01 (d, J=8.3 Hz, 2H).

EXAMPLE 3 Transactivation Test

Principle of the Test:

The activation of the receptors by an agonist (activator) in HeLa cellsresults in the expression of a reporter gene, luciferase, which, in thepresence of a substrate, generates light. It is thus possible to measurethe activation of the receptors by quantifying the luminescence producedafter incubation of the cells in the presence of a reference antagonist.The activating products displace the antagonist from its site, thusallowing activation of the receptor. The activity is measured byquantifying the increase in the light produced. This measurement makesit possible to determine the activator activity of the compound that canbe used in the invention.

In this study, a constant which represents the affinity of the moleculefor the receptor is determined. Since this value can fluctuate accordingto the basal activity and the expression of the receptor, it isdesignated apparent Kd (KdApp).

In order to determine this constant, “cross curves” of the test product(for example,4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid or4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid), against a reference antagonist otherwise known as referenceligand,4-(5,5-dimethyl-8-p-tolyl-5,6-dihydronaphthalen-2-ylethynyl)benzoicacid, are produced. The test product is used at 10 concentrations andthe reference antagonist at 7 concentrations. In each well (of a 96-wellplate), the cells are in contact with one concentration of the testproduct and one concentration of the reference antagonist.

Measurements are also carried out for the total agonist control,otherwise known as 100% control(4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)propenyl]benzoicacid), and the inverse agonist control, otherwise known as 0% control(4-{(E)-3-[4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)]-3-oxopropenyl}benzoicacid).

These cross curves make it possible to determine the AC50 values(concentration at which 50% activation of the receptor is observed) ofthe reference ligand at various concentrations of test product. TheseAC50 values are used to calculate the Schild regression by plotting astraight line corresponding to the Schild equation (“Quantitation inreceptor pharmacology” Terry P. Kenakin, Receptors and Channels, 2001,7, 371-385).

In the case of an agonist, the AC50 is calculated by plotting the curveof the product at the concentration of the reference ligand giving 80%activation. The percentage activation which corresponds to the maximumlevel of activity obtained is also measured.

Materials and Method:

The HeLa cell lines used are stable transfectants containing theplasmids ERE-βGlob-Luc-SV-Neo (reporter gene) and RAR (α, β, γ)ER-DBO-puro. These cells are seeded into 96-well plates at a rate of 10000 cells per well in 100 μl of DMEM medium without phenol red andsupplemented with 10% defatted calf serum. The plates are then incubatedat 37° C., 7% CO₂ for 4 hours.

The various dilutions of the test product, of the reference ligand

(4-(5,5-dimethyl-8-p-tolyl-5,6-dihydronaphthalen-2-ylethynyl)benzoicacid), of the 100% control (100 nM4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)propenyl]benzoicacid) and of the 0% control (500 nM4-{(E)-3-[4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)]-3-oxopropenyl}benzoicacid) are added at a rate of 5 μl per well. The plates are thenincubated for 18 hours at 37° C., 7% CO₂.

The culture medium is removed by turning the plates over, and 100 μl ofa 1:1 PBS (phosphate buffered solution)/luciferin mixture are added toeach well. After 5 minutes, the plates are read using the luminescencereader.

Results:

The values of the apparent Kd constants are indicated in the tablebelow. These values are compared to those of the compounds of WO99/10308 having the same activities.

RAR RAR beta gamma RAR alpha Kdapp Kdapp Kdapp (nM) (nM) (nM) Compoundof Example 1 15 4 0.25 Compound of Example 2 4 1 0.03 Compounds of WO99/10308: 3″-Methyl-2′-(5,5,8,8-tetramethyl- 2 1 0.255,6,7,8-tetrahydronaphthalen-2-yl)-[1,1′:4,1″]-tert-phenyl-4″-carboxylic acid (Example 41)3″-Hydroxy-2′-(5,5,8,8-tetramethyl- 2 1 0.255,6,7,8-tetrahydronaphthalen-2-yl)-[1,1′:4,1″]-tert-phenyl-4″-carboxylic acid (Example 46)2″-Methoxy-2′-(5,5,8,8-tetramethyl- 4 2 0.55,6,7,8-tetrahydronaphthalen-2-yl)-[1,1′:4,1″]-tert-phenyl-4″-carboxylic acid (Example 44)2″-Hydroxy-2′-(5,5,8,8-tetramethyl- 8 4 15,6,7,8-tetrahydronaphthalen-2-yl)-[1,1′:4,1″]-tert-phenyl-4″-carboxylic acid (Example 42)6-[2-(5,5,8,8-Tetramethyl-5,6,7,8- 4 1 1tetrahydronaphthalen-2-yl)biphenyl- 4-yl]nicotinic acid (Example 47)2′-(5,5,8,8-Tetramethyl-5,6,7,8- 2 1 1 tetrahydronaphthalen-2-yl)-[1,1′:4′,1″]-tert-phenyl-4″-carboxylic acid (Example 14)

The results obtained with4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid and4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid clearly show a better selectivity of these compounds for the gammasubtype of the RAR receptor in comparison with the other two subtypesRAR alpha and RAR beta. They also show a better activity and a betterselectivity in comparison with the most active RAR compounds describedin patent application WO 99/10308.

These compounds are therefore selective agonists or activators of theRAR gamma receptor.

EXAMPLE 4 Examples of Formulations

In this example, various specific formulations based on the compoundsaccording to the invention are illustrated.

A - ORAL ADMINISTRATION: (a) Tablet of 0.2 g:4′-(3-Hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.001 gtetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Starch 0.114 gDicalcium phosphate 0.020 g Silica 0.020 g Lactose 0.030 g Talc 0.010 gMagnesium stearate 0.005 g (b) Oral suspension in 5 ml ampoules:4′-(4-Hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.001 gtetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Glycerol 0.500 g70% sorbitol 0.500 g Sodium saccharinate 0.010 g Methylpara-hydroxybenzoate 0.040 g Flavoring qs Purified water qs 5 ml B -PARENTERAL ADMINISTRATION: (a) Composition:4′-(3-Hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.05%tetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Polyethyleneglycol   20% 0.9% NaCl solution qs 100 (b) Injectable cyclodextrincomposition: 4′-(4-Hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.1mg tetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid β-Cyclodextrin0.10 g Water for injectable preparation qs 10.00 g C - TOPICALADMINISTRATION: (a) Ointment:4′-(3-Hydroxypropoxy)-3′-(5,5,8,8-tetramethyl- 0.300 g5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Codexwhite petroleum jelly qs 100 g (b) Nonionic water-in-oil cream:4′-(4-Hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.100 gtetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Mixture ofemulsive lanolin alcohols, of waxes 39.900 g and of oils (“anhydrouseucerin” sold by BDF) Methyl para-hydroxybenzoate 0.075 g Propylpara-hydroxybenzoate 0.075 g Sterile demineralized water qs 100 g (c)Lotion: 4′-(4-Hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8- 0.100 gtetrahydronaphthalen-2-yl)biphenyl- 4-carboxylic acid Polyethyleneglycol (PEG 400) 69.900 g 95% Ethanol 30.000 g

Each patent, patent application, publication, text and literaturearticle/report cited or indicated herein is hereby expresslyincorporated by reference in its entirety.

While the invention has been described in terms of various specific andpreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

1. A method for the treatment of photoinduced or chronological skinaging, for the regulation of skin pigmentations or for the treatment ofactinic keratoses by selective agonist activity on the RAR gammareceptor, said method comprising administering to an individual in needof such treatment, a thus effective amount of a pharmaceutical orcosmetic composition which comprises a compound of the formula (I):

in which n is an integer ranging from 1 to 3 inclusive, or salt thereof,formulated into a pharmaceutically or cosmetically acceptable carrier.2. The method as defined by claim 1, wherein the compound of formula (I)is4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid.
 3. The method as defined by claim 1, wherein the compound offormula (I) is4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid.
 4. A method for the treatment of photoinduced or chronologicalskin aging by selective agonist activity on the RAR gamma receptor, saidmethod comprising administering to an individual in need of suchtreatment, a thus effective amount of a pharmaceutical or cosmeticcomposition comprising a compound of the formula (I):

in which n is an integer ranging from 1 to 3 inclusive, or salt thereof,formulated into a pharmaceutically or cosmetically acceptable carrier.5. The method as defined by claim 4, wherein the compound of formula (I)is4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid.
 6. The method as defined by claim 4, wherein the compound offormula (I) is4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid.
 7. A method for the regulation of skin pigmentations by selectiveagonist activity on the RAR gamma receptor, said method comprisingadministering to an individual in need of such treatment, a thuseffective amount of a pharmaceutical or cosmetic composition comprisinga compound of the formula (I):

in which n is an integer ranging from 1 to 3 inclusive, or salt thereof,formulated into a pharmaceutically or cosmetically acceptable carrier.8. The method as defined by claim 7, wherein the compound of formula (I)is4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid.
 9. The method as defined by claim 7, wherein the compound offormula (I) is4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid.
 10. A method for the treatment of actinic keratoses by selectiveagonist activity on the RAR gamma receptor, said method comprisingadministering to an individual in need of such treatment, a thuseffective amount of a pharmaceutical or cosmetic composition comprisinga compound of the formula (I):

in which n is an integer ranging from 1 to 3 inclusive, or salt thereof,formulated into a pharmaceutically or cosmetically acceptable carrier.11. The method as defined by claim 10, wherein the compound of formula(I) is4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid.
 12. The method as defined by claim 10, wherein the compound offormula (I) is4′-(4-hydroxybutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylicacid.